Constitutive Activation of Kappa Opioid Receptors at Ventral Tegmental Area

RESEARCH ARTICLE Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress Abigail M Polter1†, Kelsey Barcomb1, Rudy W Chen1, Paige M Dingess2,3, Nicholas M Graziane1‡, Travis E Brown2,3, Julie A Kauer1* 1Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, United States; 2Neuroscience Program, University of Wyoming, Laramie, United States; 3University of Wyoming, School of Pharmacy, Laramie, United States Abstract Stressful experiences potently activate kappa opioid receptors (kORs). kORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of kORs. This is mediated *For correspondence: by activation of the receptor during the stressor followed by a persistent, ligand-independent [email protected] constitutive activation of the kOR itself. This lasting change in function is not seen at kORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of Present address: †Department different subsets of kORs. We also provide evidence that constitutive activity of kORs governs the of Pharmacology and Physiology, The George Washington prolonged reinstatement to cocaine-seeking observed after cold water swim stress. Together, our University School of Medicine studies indicate that stress-induced constitutive activation is a novel mechanism of kOR regulation and Health Science, Washington, that plays a critical role in reinstatement of drug seeking. United States; ‡Department of DOI: 10.7554/eLife.23785.001 Neuroscience, University of Pittsburgh, Pittsburgh, United States Competing interests: The Introduction authors declare that no Stress has long been known to be a precipitating factor for the abuse of addictive drugs. Animal competing interests exist. models have shown that acute and repeated stressors can escalate intake of addictive substances (Piazza et al., 1990; Ramsey and Van Ree, 1993; Goeders and Guerin, 1994; Shaham and Stew- Funding: See page 17 art, 1994; Haney et al., 1995), and that acute stress can reinstate drug seeking in animals that have Received: 30 November 2016 undergone extinction training (Shaham et al., 1994, 1995; Conrad et al., 2010; Mantsch et al., Accepted: 13 March 2017 2016). In recent years, dopaminergic neurons of the VTA have emerged as a significant locus for the Published: 12 April 2017 overlapping effects of drugs of abuse and stress (Polter and Kauer, 2014). Synaptic inputs, by shap- Reviewing editor: Lisa M ing the activity of these neurons, are poised to play an important role in drug seeking. Both acute Monteggia, University of Texas stress and exposure to drugs of abuse induce a concomitant potentiation of excitatory synapses and Southwestern Medical Center, loss of long term potentiation of inhibitory synapses (Ungless et al., 2001; Saal et al., 2003; United States Kauer and Malenka, 2007; Nugent et al., 2007; Chen et al., 2008; Niehaus et al., 2010; Polter and Kauer, 2014). Understanding how these synapses are altered by stress will provide key Copyright Polter et al. This insights into stress-induced drug seeking and provide targets for treating substance use disorders. article is distributed under the A major mediator of stress-induced changes in inhibitory VTA synapses is the dynorphin/kappa terms of the Creative Commons Attribution License, which opioid receptor (kOR) system. kORs, and their endogenous ligand, dynorphin, are found throughout permits unrestricted use and the brain and have been highly associated with stressful, aversive, and dysphoric experiences redistribution provided that the (Bruchas et al., 2010; Wee and Koob, 2010; Van’t Veer and Carlezon, 2013; Crowley and Kash, original author and source are 2015). Within the VTA, kORs have a range of physiological effects. kORs decrease the firing rate of credited. dopamine neurons through activation of GIRK channels (Margolis et al., 2003, 2006), inhibit Polter et al. eLife 2017;6:e23785. DOI: 10.7554/eLife.23785 1 of 21 Research article Neuroscience eLife digest People who are recovering from drug addiction are more vulnerable to cravings and relapse when under stress. This ability of stress to boost drug relapse can also be shown in animals previously exposed to addictive drugs. Rats can learn to press a lever to administer themselves a dose of cocaine and, during withdrawal, rats previously exposed to the drug will press the lever more often if they are stressed. Indeed, just a few minutes of stress is enough to increase lever pressing for several days. Stress and addictive drugs both act on a region of the brain called the ventral tegmental area, or VTA, which is part of the brain’s reward system. Stress indirectly increases the activity of the VTA. It does so by activating a protein on the surface of VTA neurons called the kappa opioid receptor (kOR for short). Previous studies revealed that five minutes of stress increases the activity of kORs in the VTA of rats for five days. Conversely, blocking kORs stopped stressed rats from pressing the lever more often for cocaine. Together, these findings suggested that activating kORs in the VTA contributes to stress-induced drug relapse. Polter et al. have now discovered how stress activates kORs. It turns out that stressful or unpleasant experiences cause the brain to produce a protein called dynorphin, which binds to and activates the kORs. After a stressful event, the receptors are said to have become constitutively active, and blocking this constitutive activity prevents stress from inducing drug-seeking behavior. Polter et al. show that binding of dynorphin is needed to change the shape of the receptors so that they remain active even after dynorphin has detached, but it is likely that other molecules are also involved. This is the first study to show a link between stress, constitutive activation of kORs, and drug relapse. The next step is to work out why this process occurs on only some and not all occasions when the brain releases dynorphin, and why only certain kORs in the VTA respond in this way. Whether constitutive kOR activity drives stress-related craving in people with a history of drug abuse and how to halt these cravings also remain to be determined. DOI: 10.7554/eLife.23785.002 excitatory synaptic transmission onto both dopaminergic and non-dopaminergic VTA neurons (Margolis et al., 2005), reduce inhibitory synaptic transmission in a subset of dopamine neurons (Ford et al., 2006) and inhibit somatodendritic dopaminergic IPSCs (Ford et al., 2007). VTA kORs also can control the interactions between stress and reward. Our previous work identified a form of stress-sensitive synaptic plasticity at inhibitory synapses on VTA dopamine neurons (LTPGABA; Nugent et al., 2007, 2009; Niehaus et al., 2010). LTPGABA is induced via activation of nitric oxide synthase in the dopamine neuron, leading to nitric oxide (NO) release, and enhancement of GABA release through cGMP signaling (Nugent et al., 2007, 2009). More recently, we showed that acute stress blocks LTPGABA through activation of kORs, and that preventing this activation via intra-VTA administration of the kOR antagonist, nor-binaltorphimine (norBNI), prevents stress-induced reinstatement of cocaine-seeking (Graziane et al., 2013). Remark- ably, a single exposure to stress leads to a loss of LTPGABA that lasts for at least five days and is mediated by persistent activation of VTA kORs (Polter et al., 2014). We have also shown that treat- ment with the kOR antagonist after stress can rescue stress-induced reinstatement. These studies highlight the importance of kOR-mediated regulation of LTP at GABAergic synapses in stress- induced drug seeking and underscore the need to better understand the mechanism of this unique and persistent regulation. In the present study, we have now identified the mechanism by which activation of kORs and sup- pression of LTPGABA in the VTA is maintained for multiple days after an acute, severe stressor. We present evidence that stress blocks LTPGABA by inducing constitutive activation of kORs at VTA inhibitory synapses rather than through persistent increases in dynorphin release. This constitutive activity is likely to be triggered initially by signaling through the endogenous ligand dynorphin, but then is persistently maintained independently of dynorphin release. In parallel, we find that the persistent drug-seeking induced by a single exposure to acute stress is also dependent on constitutive activity of kORs. Our results reveal a novel mechanism of experience-dependent regulation of kOR Polter et al. eLife 2017;6:e23785. DOI: 10.7554/eLife.23785 2 of 21 Research article Neuroscience function, and emphasize the essential role of kORs in mediating stress-induced changes in synaptic plasticity and drug-seeking behavior. Results JNK-dependent rescue of LTPGABA by acute norBNI As previously shown, bath application of the nitric oxide donor SNAP potentiates GABAergic synapses on dopamine neurons in the VTA, similarly to high-frequency stimulation of VTA afferents; this potentiation is blocked by single exposure to multiple drugs of abuse or acute cold-water swim stress (LTPGABA; Nugent et al., 2007; Niehaus et al., 2010; Graziane et al., 2013; Polter et al., 2014; Figure 1A–B). Our recent studies indicate that blocking kORs with

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